August 14 2008 hiv and hepatitis chia wang md
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August 14, 2008 HIV and Hepatitis Chia Wang, MD. Hepatitis B and C. Chia C. Wang, MD, MS Clinical Assistant Professor of Medicine University of Washington. Outline. Quick review of Hepatitis B Staging infection Cases and Quiz---stage the infection Hepatitis C case

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August 14 2008 hiv and hepatitis chia wang md

August 14, 2008

HIV and Hepatitis

Chia Wang, MD


Hepatitis b and c

Hepatitis B and C

Chia C. Wang, MD, MS

Clinical Assistant Professor of Medicine

University of Washington


Outline

Outline

  • Quick review of Hepatitis B

    • Staging infection

    • Cases and Quiz---stage the infection

  • Hepatitis C case

    • New therapies for hepatitis C


Hbv serologies

HBV Serologies


Using blood tests to stage hepatitis b infection

Viral envelope

Viral surface

Viral DNA

Viral core

Using blood tests to stage hepatitis B infection


Hbv markers

Slide courtesy of Ray Kim, Mayo clinic

HBV Markers

Anti-HBs+

HBV Infection

present

Immunity

HBsAg+

Exposure to HBV

Anti-HBc+


What is the significance of hepatitis b eag

What is the significance of hepatitis B eAg?

  • The presence of HBeAg signifies a high circulating HBV DNA

  • The clearance of HBeAg is an important endpoint of treatment

  • Patients without HBeAg are not infectious

  • HBeAg is a protein secreted by the hepatitis B virus


3 categories of hepatitis b

3 categories of hepatitis B

  • Acute hepatitis B

    • HBsAg+, HB core IgM Ab+, HBsAb-

  • Resolved hepatitis B

    • HBsAb+, HB total core Ab+, HBsAg-

  • Chronic hepatitis B

    • Inactive hepatitis B

    • Active hepatitis B

      • eAg positive hepatitis B

      • eAg negative hepatitis B

    • Hepatitis B and cirrhosis


3 categories of hepatitis b1

3 categories of hepatitis B

  • Acute hepatitis B

    • HBsAg+, HB core IgM Ab+, HBsAb-

  • Resolved hepatitis B

    • HBsAb+, HB total core Ab+, HBsAg-

  • Chronic hepatitis B

    • Inactive hepatitis B

    • Active hepatitis B

      • eAg positive hepatitis B

      • eAg negative hepatitis B

    • Hepatitis B and cirrhosis


3 categories of hepatitis b2

3 categories of hepatitis B

  • Acute hepatitis B

    • HBsAg+, HB core IgM Ab+, HBsAb-

  • Resolved hepatitis B

    • HBsAb+, HB total core Ab+, HBsAg-

  • Chronic hepatitis B

    • Inactive hepatitis B

    • Active hepatitis B

      • eAg positive hepatitis B

      • eAg negative hepatitis B

    • Hepatitis B and cirrhosis


Inactive chronic hepatitis b

Asymptomatic

Titer

HBsAg

HBV DNA

HBeAg

32

24

0

8

4

12

20

28

36

52

100

16

Inactive chronic hepatitis B

10,000 copies/ml or 2,000 IU/ml


Inactive chronic hepatitis b1

Inactive chronic hepatitis B

  • HBsAg+

  • HB total core Ab+

  • HBeAg-

  • HBV DNA <2000 IU/ml (10,000 copies/ml)


3 categories of hepatitis b3

3 categories of hepatitis B

  • Acute hepatitis B

    • HBsAg+, HB core IgM Ab+, HBsAb-

  • Resolved hepatitis B

    • HBsAb+, HB total core Ab+, HBsAg-

  • Chronic hepatitis B

    • Inactive hepatitis B

    • Active hepatitis B

      • eAg positive hepatitis B

      • eAg negative hepatitis B

    • Hepatitis B and cirrhosis


Active eag chronic hepatitis b

32

52

36

28

24

20

100

12

4

8

0

16

Active eAg+ chronic hepatitis B

May be symptomatic

Titer

HBsAg

HBV DNA

HBeAg

10,000 copies/ml or 2,000 IU/ml


Active eag chronic hepatitis b1

Active eAg+ chronic hepatitis B

  • HBsAg+

  • HB total core Ab+

  • HBeAg+

  • HBV DNA >2000 IU/ml (10,000 copies/ml)


Chronic hepatitis b

1

6

2

4

5

20

3

8

9

10

30

7

Chronic hepatitis B

Sx

Sx

Sx

Sx

HBsAg

Titer

HBV DNA and ALT

Years


3 categories of hepatitis b4

3 categories of hepatitis B

  • Acute hepatitis B

    • HBsAg+, HB core IgM Ab+, HBsAb-

  • Resolved hepatitis B

    • HBsAb+, HB total core Ab+, HBsAg-

  • Chronic hepatitis B

    • Inactive hepatitis B

    • Active hepatitis B

      • eAg positive hepatitis B

      • eAg negative hepatitis B

    • Hepatitis B and cirrhosis


Core promoter and precore mutants

Core promoter and precore mutants

Core promoter mutation

Down regulation of eAg production

Precore mutation

Abolishment of eAg production


Active eag chronic hepatitis b2

32

52

36

28

24

20

100

12

4

8

0

16

Active eAg- chronic hepatitis B

May be symptomatic

Titer

HBsAg

HBV DNA

10,000 copies/ml or 2,000 IU/ml

HBeAg


Active eag chronic hepatitis b3

Active eAg- chronic hepatitis B

  • HBsAg+

  • HB total core Ab+

  • HBeAg-

  • HBV DNA >2000 IU/ml (10,000 copies/ml)


Active versus inactive chronic hepatitis b

Asymptomatic

Titer

HBsAg

HBV DNA

HBeAg

10,000 copies/ml or 2,000 IU/ml

12

100

52

36

24

28

36

16

52

32

4

8

28

20

32

100

20

16

24

4

8

0

0

12

Active versus inactive chronic hepatitis B

May be symptomatic

Titer

HBsAg

HBV DNA

10,000 copies/ml or 2,000 IU/ml

HBeAg


3 categories of hepatitis b5

3 categories of hepatitis B

  • Acute hepatitis B

    • HBsAg+, HB core IgM Ab+, HBsAb-

  • Resolved hepatitis B

    • HBsAb+, HB total core Ab+, HBsAg-

  • Chronic hepatitis B

    • Inactive hepatitis B

    • Active hepatitis B

      • eAg positive hepatitis B

      • eAg negative hepatitis B

    • Hepatitis B and cirrhosis


Chronic hepatitis b and cirrhosis

Chronic hepatitis B and cirrhosis

  • Any patient with cirrhosis who is HBsAg+ and has a detectable HBV DNA should be treated


Cases

Cases


Case 1

Case 1

  • A 16 year old Ethiopian boy is being evaluated for immigration to the United States

  • He is HIV negative, but HBsAg positive

  • His liver enzymes and synthetic function are normal


Which of the following tests do you need to stage his infection

Which of the following tests do you need to stage his infection?

  • Hepatitis B core Ab

  • Hepatitis B surface Ab

  • Hepatitis B eAg and eAb

  • HBV DNA


Case 1 lab results

Case 1 lab results

  • Hepatitis B eAg negative

  • Hepatitis B eAb positive

  • HBV DNA 100 IU/ml


What stage of hepatitis b is the patient in

What stage of hepatitis B is the patient in?

  • Chronic inactive hepatitis B

  • Chronic eAg positive hepatitis B

  • Chronic eAg negative hepatitis B


Which of the following is true for this patient

Which of the following is true for this patient?

  • He needs no treatment for his hepatitis B infection

  • His risk of liver cancer is lower than someone with HBeAg+ hepatitis B

  • His risk of liver cancer is higher than someone with HBsAb+ hepatitis B

  • He does not need to be screened for liver cancer, because he has inactive disease


Liver cancer

Liver Cancer


Aasld recommendations for screening for liver cancer

AASLD recommendations for screening for liver cancer

  • HBsAg positive Africans starting at age 20

  • HBsAg positive Asian men starting at age 40

  • HBsAg positive Asian women at age 50

  • Any HBsAg positive patient with cirrhosis

  • Any HBsAg positive patient with a family history of liver cancer

  • Genotype C----- start screening earlier?


Case 2

Case 2

  • A 44 year old man with HIV is being evaluated

  • HIV positive

    • CD4 300, HIV viral load 100,000 copiesml

  • HBsAg positive

    • HBeAg negative, HBeAb positive


Which of the following tests do you need to stage his infection1

Which of the following tests do you need to stage his infection?

  • Hepatitis B core Ab

  • Hepatitis B surface Ab

  • Hepatitis B eAg and eAb

  • HBV DNA


Case 2 lab results

Case 2 lab results

  • HBV DNA 1million IU/ml

  • ALT 120, AST 80

  • Albumin 4.0

  • Total bilirubin 1.0


What stage of hepatitis b is the patient in1

What stage of hepatitis B is the patient in?

  • Chronic inactive hepatitis B

  • Chronic eAg positive hepatitis B

  • Chronic eAg negative hepatitis B


Which of the following is true for this patient1

Which of the following is true for this patient?

  • He needs no treatment for his hepatitis B infection

  • He needs a liver biopsy before deciding about hepatitis B treatment

  • When choosing treatment for HIV infection, antivirals that also treat Hepatitis B should be selected

  • Screening for liver cancer should be initiated immediately


Which of the following hiv meds also treat hepatitis b

Which of the following HIV meds also treat hepatitis B?

  • Tenofovir

  • Abacavir

  • Lamivudine

  • AZT


Case 3

Case 3

  • A 38 year old woman is found to be HIV positive and HBsAg+

  • CD4 count = 250, HIV viral load 80,000 copies/ml

  • Hepatitis B

    • HBsAg +

    • HBeAb+

    • HBV DNA 1000 IU/ml


What stage of hepatitis b is the patient in2

What stage of hepatitis B is the patient in?

  • Chronic inactive hepatitis B

  • Chronic eAg positive hepatitis B

  • Chronic eAg negative hepatitis B


Case 3 lab results

Case 3 lab results

  • ALT=60

  • AST=80

  • Albumin 3.0

  • T. Bilirubin 2.0

  • Platelet count 80,000


Gross pathology of cirrhosis

Gross pathology of cirrhosis

Normal liver

Fibrotic liver

Courtesy of: http://www.meddean.luc.edu/lumen/MedEd/orfpath/cirhosis.html


Which of the following is true for this patient2

Which of the following is true for this patient?

  • She needs no treatment for his hepatitis B infection because she is in the inactive stage of infection

  • She is at high risk to develop liver cancer

  • When selecting treatment for HIV, antiviral medications should be chosen that also are effective against HBV


Hepatitis c

Hepatitis C


Case 4

Case 4

  • A 48 year old HIV-negative man is found to be Hepatitis C antibody positive

  • Hepatitis C viral load is 1 million IU/ml

  • Hepatitis C genotype is genotype 1


Case 4 continued

Case 4, continued

  • Therapy for hepatitis C is initiated with pegylated interferon/ribavirin

  • At 12 weeks, hepatitis C viral load is 100,000 IU/ml

  • In addition, the patient suffers from terrible side effects

    • Nausea

    • Hair loss

    • Itching

    • Depression/irritability

    • Fatigue

    • Insomnia


Responses to therapy

Responses to therapy

  • Sustained virologic response

    • Negative viral load 6-months after completing treatment

  • Relapse

    • -- Recurrence of viral load after initial disappearance

  • Non-response/partial response

    • -- Viral load never drops or drops by > 2 logs but never disappears


August 14 2008 hiv and hepatitis chia wang md

RELAPSE

NON-RESPONSE

SUSTAINED RESPONSE

Lower limit of detectable virus

6 months

12 months

18 months

Hepatitis C: Patterns of Response to Treatment

*


Evolution of treatment for hepatitis c

Evolution of treatment for hepatitis C

McHutchinson, et al. NEJM 1998;339:1485-92

Zeuzem, et al. NEJM 2000;343:1666-1672

Manns, MP et al. Lancet 2001;358:958-865


Pegasys prefilled syringe

Pegasys Prefilled Syringe


Side effects of ifn

Flu-like symptoms

fatigue

myalgias

arthralgias

headache

fever, chills

dehydration

weight loss

Psychiatric symptoms

depression

mood lability

anxiety

insomnia

impaired concentration

Ophthalmologic

retinal disease

Side Effects of IFN


Side effects of ifn page 2

Gastrointestinal

diarrhea

nausea

vomiting

abdominal pain

anorexia

aphthous ulcers

dyspepsia

Respiratory

cough

dyspnea

Dermatologic

rash

alopecia

pruritis

dry skin

injection site reaction

Autoimmunity

thyroiditis

psoriasis

Side Effects of IFN (page 2)


Side effects of ifn page 3

Hematologic

anemia

neutropenia

thrombocytopenia

Side Effects of IFN (page 3)


Side effects of rbv

Side Effects of RBV

  • Hemolytic anemia

  • Teratogenicity

  • Cough and dyspnea

  • Rash and pruritus

  • Insomnia

  • Anorexia

Rebetron [package insert]. Kenilworth, NJ: Schering Corp; 1999.


Interferon man

Interferon-man


Peg 40 kda ifn alfa 2a rbv 12 week negative predictability analysis

PEG (40 kDa) IFN alfa-2a/RBV12-Week Negative Predictability Analysis

Week 12 (n = 453)

(n = 253)65%

SVR

Yes

(n = 390) 86%

No SVR

(n = 137) 35%

2 Log10 Dropor Neg HCV RNA

(n = 2)3%

SVR

(n = 63)14%

No SVR

No

(n = 61) 97%

HCV = hepatitis C virus; RNA = ribonucleic acid; SVR = sustained virologic response.

Fried et al. DDW; May 20-23, 2001; Atlanta, Ga.


Which of the following is true for this patient3

Which of the following is true for this patient?

  • He should be told that he is interferon-nonresponder, and therapy should be discontinued immediately

  • He should be told that he is interferon-nonresponder, and offered to option to continue medication for 48 weeks

  • He should stop therapy, and be encouraged that new treatments for hepatitis C are being developed, so that future regimens will be easier to tolerate


August 14 2008 hiv and hepatitis chia wang md

Polymerase

Protease


Translation

Translation

An enzyme called a protease is necessary to slice up the large polyprotein into smaller proteins


Vx 950 a protease inhibitor the promise

VX-950– A protease inhibitor—The promise

1

0

-1

Median HCV RNA Changefrom Baseline (Log10 IU/mL)

-2

-3

-4

-5

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Study Time (in Days)

Placebo

VX-950 750 mg q8h

VX-950 1250 mg q12h

VX-950 450 mg q8h

Reesink et al. DDW. 2005.


Evaluating resistance patterns to vx 950

placebo (n=6)

breakthrough (n=13)

plateau (n=8)

continuous decline (n=7)

Evaluating Resistance Patterns to VX-950

Long-termfollow-up

-

-

-

-

-

-

-

-

Dosing with VX

950

Slow return post

dosing

7

7

7

6

6

6

6

5

5

5

5

4

4

4

Median Log HCV RNA

3

3

3

3

2

2

2

2

1

1

1

1

0

0

0

0

0

0

0

0

3-7 months

14

0

0

0

0

2

2

2

4

4

4

4

6

6

6

8

8

8

8

10

10

10

10

12

12

12

12

12

12

12

16

16

16

16

18

18

18

18

18

18

18

18

20

20

20

20

22

22

22

2

24

24

24

26

26

26

26

28

28

28

28

Time (days)

10

Kieffer et al. EASL 2006


August 14 2008 hiv and hepatitis chia wang md

7

6

5

4

3

2

1

156

36/155

WT

36

54

WT

156

155

155

54

36

36/155

V36

M/A/L

R155

K/T/S/M

IC50 fold change

36/155

A156V/T

36/156

T54A

WT

1 4 7 12 46 466 781

Emergence of Resistance Underlies Breakthrough and Plateau Response

VX-950 Dosing Period

Post-Dosing

Long-term follow-up

Median Log HCV RNA

Long-term follow-up

3-7 months post-dosing

Follow-Up

7/10 days post-dosing

EOD 14 days

Baseline

155

36

WT

WT


Clinical implications

Clinical Implications

  • Resistance will limit the use of oral inhibitors as a monotherapy


August 14 2008 hiv and hepatitis chia wang md

The Future Of HCV Therapy

Viral enzyme

inhibitors

Immune

modulation

+

+

Ribavirin or

related drugs

Interferon as a platform for future combinations


August 14 2008 hiv and hepatitis chia wang md

Next session: August 21, 2008

Listserv: [email protected]

Email: [email protected]


Next session august 21 2008 scott mcclelland md hiv and women

Next session: August 21, 2008

Scott McClelland, MD

HIV and Women


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